Nitrite-mediated renal vasodilatation is increased during ischemic conditions via cGMP-independent signaling

Liu, Ming; Zollbrecht, Christa; Peleli, Maria; Lundberg, Jon O.; Weitzberg, Eddie; Carlström, Mattias

doi:10.1016/j.freeradbiomed.2015.03.025

Cited by 28 publications

(35 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to what has been proposed in some studies using inorganic nitrate or nitrite, it is possible that NDBP‐mediated effects to some extent are cGMP‐independent (e.g. via formation of nitros(yl)ation products), which has been proposed for nitrate‐mediated vascular (Carlstrom et al , ; Liu et al , ) and metabolic effects (Carlstrom et al , ).…”

Section: Discussionsupporting

confidence: 62%

“…All preparations were stabilized under a resting tension of 0.75 g for 1 h, and the solution was replaced every 15 min in order to prevent the accumulation of metabolites (first stabilization). The force of contraction was isometrically recorded by a tension transducer (PowerLab™, ADInstruments, MA, USA), as described previously (Liu et al , ). Tissue viability was verified by the presence of a contraction to phenylephrine (PE, 10 μM) added to the bath, and successful removal of the endothelium was verified by the absence of a response to ACh (10 μM), as previously described (Franca‐Silva et al , ).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II‐mediated hypertension

Porpino

Zollbrecht

Peleli

et al. 2016

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

*Equal contribution. BACKGROUND AND PURPOSENO deficiency and oxidative stress are crucially involved in the development or progression of cardiovascular disease, including hypertension and stroke. We have previously demonstrated that acute treatment with the newly discovered organic nitrate, 2-nitrate-1,3-dibuthoxypropan (NDBP), is associated with NO-like effects in the vasculature. This study aimed to further characterize the mechanism(s) and to elucidate the therapeutic potential in a model of hypertension and oxidative stress. EXPERIMENTAL APPROACHA combination of ex vivo, in vitro and in vivo approaches was used to assess the effects of NDBP on vascular reactivity, NO release, NADPH oxidase activity and in a model of hypertension. KEY RESULTSEx vivo vascular studies demonstrated NDBP-mediated vasorelaxation in mesenteric resistance arteries, which was devoid of tolerance. In vitro studies using liver and kidney homogenates revealed dose-dependent and sustained NO generation by NDBP, which was attenuated by the xanthine oxidase inhibitor febuxostat. In addition, NDBP reduced NADPH oxidase activity in the liver and prevented angiotensin II-induced activation of NADPH oxidase in the kidney. In vivo studies showed that NDBP halted the progression of hypertension in mice with chronic angiotensin II infusion. This was associated with attenuated cardiac hypertrophy, and reduced NADPH oxidase-derived oxidative stress and fibrosis in the kidney and heart. CONCLUSION AND IMPLICATIONSThe novel organic nitrate NDBP halts the progression of angiotensin II-mediated hypertension. Mechanistically, our findings suggest that NDBP treatment is associated with sustained NO release and attenuated activity of NADPH oxidase, which to some extent requires functional xanthine oxidase. AbbreviationsANG II, angiotensin II; DHE, dihydroethidium; NADPH, nicotinamide adenine dinucleotide phosphate; NOX, NADPH oxidase; NDBP, 2-nitrate-1,3-dibuthoxypropan; NTG, nitroglycerin; PE, phenylephrine; XO, xanthine oxidase

show abstract

Section: Discussionsupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II‐mediated hypertension

Porpino

Zollbrecht

Peleli

et al. 2016

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The NO 3 - -NO 2 - -NO pathway is greatly enhanced in conditions with ischemia and hypoxia when NOS-dependent NO generation is compromised [22], [23]. In an ex vivo setting we have previously reported that the renal microvasculature is exquisitely responsive to nitrite-mediated vasodilatation [35] and that the effects of nitrite are significantly enhanced at lower pH and oxygen tensions mimicking the in vivo ischemic environment [42]. Dietary sources of nitrate can thus serve as an ideal alternative NO progenitor pool during tissue IR injury.…”

Section: Discussionmentioning

confidence: 99%

Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress

et al. 2017

Self Cite

View full text Add to dashboard Cite

Ischemia-reperfusion (IR) injury involves complex pathological processes in which reduction of nitric oxide (NO) bioavailability is suggested as a key factor. Inorganic nitrate can form NO in vivo via NO synthase-independent pathways and may thus provide beneficial effects during IR. Herein we evaluated the effects of dietary nitrate supplementation in a renal IR model. Male mice (C57BL/6J) were fed nitrate-supplemented chow (1.0 mmol/kg/day) or standard chow for two weeks prior to 30 min ischemia and during the reperfusion period. Unilateral renal IR caused profound tubular and glomerular damage in the ischemic kidney. Renal function, assessed by plasma creatinine levels, glomerular filtration rate and renal plasma flow, was also impaired after IR. All these pathologies were significantly improved by nitrate. Mechanistically, nitrate treatment reduced renal superoxide generation, pro-inflammatory cytokines (IL-1β, IL-6 and IL-12 p70) and macrophage infiltration in the kidney. Moreover, nitrate reduced mRNA expression of pro-inflammatory cytokines and chemo attractors, while increasing anti-inflammatory cytokines in the injured kidney. In another cohort of mice, two weeks of nitrate supplementation lowered superoxide generation and IL-6 expression in bone marrow-derived macrophages. Our study demonstrates protective effect of dietary nitrate in renal IR injury that may be mediated via modulation of oxidative stress and inflammatory responses. These novel findings suggest that nitrate supplementation deserve further exploration as a potential treatment in patients at high risk of renal IR injury.

show abstract

“…This is based on studies showing the absence of effects of nitrite in the presence of ODQ. However, this is complicated by the results of a very recent study showing that nitrite‐dependent dilatation under hypoxic conditions was ODQ‐insensitive in the low physiological ranges of nitrite .…”

Section: Cardiovascular Effects Of Nitrate and Nitritementioning

confidence: 99%

Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases

et al. 2015

View full text Add to dashboard Cite

Abstract. Omar SA, Webb AJ, Lundberg JO, Weitzberg E (Karolinska Institutet, Stockholm, Sweden; and King's College London British Heart Foundation Centre, London, UK). Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases (Review). J Intern Med 2016; 279: 315-336.Nitric oxide (NO) is generated endogenously by NO synthases to regulate a number of physiological processes including cardiovascular and metabolic functions. A decrease in the production and bioavailability of NO is a hallmark of many major chronic diseases including hypertension, ischaemia-reperfusion injury, atherosclerosis and diabetes. This NO deficiency is mainly caused by dysfunctional NO synthases and increased scavenging of NO by the formation of reactive oxygen species. Inorganic nitrate and nitrite are emerging as substrates for in vivo NO synthase-independent formation of NO bioactivity. These anions are oxidation products of endogenous NO generation and are also present in the diet, with green leafy vegetables having a high nitrate content. The effects of nitrate and nitrite are diverse and include vasodilatation, improved endothelial function, enhanced mitochondrial efficiency and reduced generation of reactive oxygen species. Administration of nitrate or nitrite in animal models of cardiovascular disease shows promising results, and clinical trials are currently ongoing to investigate the therapeutic potential of nitrate and nitrite in hypertension, pulmonary hypertension, peripheral artery disease and myocardial infarction. In addition, the nutritional aspects of the nitratenitrite-NO pathway are interesting as diets suggested to protect against cardiovascular disease, such as the Mediterranean diet, are especially high in nitrate. Here, we discuss the potential therapeutic opportunities for nitrate and nitrite in prevention and treatment of cardiovascular and metabolic diseases.

show abstract

Nitrite-mediated renal vasodilatation is increased during ischemic conditions via cGMP-independent signaling

Cited by 28 publications

References 34 publications

Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II‐mediated hypertension

Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II‐mediated hypertension

Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress

Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases

Contact Info

Product

Resources

About